Proteolytic antibodies ("Proteo-abzymes") are a novel therapeutic modality that has the potential to revolutionize antibody-based therapeutics. The overall goal of this project is to develop potent proteolytic anti-amphiregulin (AR) human monoclonal antibodies (HMAbs). Psoriasis is an ideal target for this approach. Several recent studies demonstrate a key role for AR in the pathogenesis of psoriasis. Transgenic mice bearing the AR gene expressed in keratinocytes develop a skin disease with features strikingly similar to human psoriasis (Cook, 1997; 2004). Most importantly for the present approach, neutralizing anti-AR antibodies given i.p. at high doses alleviate the characteristic lesions in affected human psoriatic skin transplanted onto immunocompromised mice (Bhagavathula, 2005). However, grams of passively administered antibodies will be required for chronic therapy, a definite limitation of the traditional HMab approach. We hypothesize that a proteolytic anti-amphiregulin antibody can mediate a similar beneficial effect at a dose 3-4 logs below conventional antibodies. The passive immunotherapy of psoriasis will become practical with the proteo-abzyme approach. The goal of phase I is to construct a proteolytic anti-AR HMab and begin in vitro characterization. In phase II we will carry out more extensive cell culture and animal validation studies in order to support submission of an IND. [unreadable] [unreadable] [unreadable]